The precise organization of subcellular organelles is important for maintaining cellular homeostasis. Compartmentalization orchestrates metabolic processes, signal transductions, and stress responses. Disturbances in organelles, including the nucleus, mitochondria, lysosomes, and endoplasmic reticulum, can lead to widespread intracellular dysfunction and contribute to diverse pathologies. For example, mitochondrial reactive oxygen species (ROS) exacerbate endoplasmic reticulum (ER) stress, as demonstrated in studies linking ROS-mediated mitochondrial dysfunction to apoptosis in neurodegenerative diseases, cancer, and inflammatory diseases [1–4]. ER stress has also been implicated in cardiac hypertrophy [5], lung fibrosis [6], liver fibrosis [7], and ulcerative colitis [8].

Emerging evidence highlights ferroptosis as a “double-edged sword” in tumor immunity, closely tied to the tumor microenvironment [9]. Mitochondria-targeted therapies, such as Mitoquinone for cigarette smoke-induced airway inflammation [10,11] and Mesaconine for PINK1-dependent mitophagy in doxorubicin-induced cardiotoxicity [12], underscore the therapeutic potential for restoring mitochondrial homeostasis. Additionally, lysosomal impairment obstructs autophagic clearance of damaged organelles, as seen in Parkinson’s disease models where defective lysosomal degradation promotes protein aggregation [13–15]. Nanomedicine based approaches, such as autophagy-activating aluminum hydroxide nanovaccines, have been developed to enhance antigen presentation in tumor immunotherapy [16,17]. Conversely, lysosomal autophagy inhibition by hydroxychloroquine [18], nanoparticles [19], or small-molecule kinase modulators [20] demonstrates the dual role of lysosomal pathways in disease modulation.

Despite extensive research, the mechanistic links between organelle dysfunction and disease progression remain only partially elucidated. This special issue brings together recent advances in subcellular biology, focusing on the regulatory mechanisms underlying organelle dysfunction and its pathophysiological implications. The collection includes studies that dissect organelle-specific pathologies, explore cross-compartmental interactions, and suggest novel therapeutic strategies.

The interdependence of organelles is evident in pathologies such as ferroptosis, where mitochondrial lipid peroxidation and lysosomal membrane destabilization converge [29–32]. Targeting these pathways, such as activating Nrf2 to mitigate oxidative stress [29,33–36], offers promising therapeutic avenues. Furthermore, non-coding RNAs (e.g., uc.243 in ovarian cancer chemoresistance) and epigenetic modifiers (e.g., METTL3-mediated m6A in cholangiocarcinoma) exemplify nuclear-cytoplasmic crosstalk in disease progression [29].

The studies presented in this issue underscore that organelle dysfunction is rarely an isolated event. Rather, it initiates cross-compartmental cascades that exacerbate disease progression. For example, mitochondrial ROS may amplify ER stress, while lysosomal impairment can obstruct the autophagic clearance of damaged organelles [37]. These interdependencies offer promising translational avenues: targeting specific pathways such as RFX5 in asthma, LGALS2 in OSCC, CKLF1 in myocardial infarction could facilitate precision medicine approaches. In addition, leveraging immune-related lncRNAs in DCM, employing mitochondrial antioxidants in kidney disease [38], stabilizing lysosomes in acute pancreatitis [39], and modulating ferroptosis in cancer [29,31,32] represent promising therapeutic avenues.

Collectively, the insights presented in this issue not only enhance our understanding of organelle dysfunction in a variety of disorders but also pave the way for novel diagnosis and therapeutic strategies, highlighting the need for continued exploration in this evolving field.

Wu Y, Dai T, Qin J, Guo J, Fan J, Mei J, et al. Regulation of dendritic cell function by RFX5 through interaction with HDAC2 and its mechanism in pediatric asthma. BIOCELL. 2025;49(4):701–20.